Freeze-drying or lyophilization has been widely used for a number of decades in pharmaceutical, food, and chemical industries. Freeze-drying is particularly desirable in situations where a pharmaceutical or other material is required to be dried or dehydrated or desolvated, but is sensitive to the application of heat for the purpose of drying. Many compounds, when exposed to the typically employed drying temperatures of non-freeze drying techniques, decompose, degrade, or volatilize away, resulting in an undesirable product. To recognize the large number of applications to which freeze-drying has been adapted, one need only run a simple search of the US Patent and Trademark Office patent databases for the term “freeze drying” and/or “lyophilization”, which as of October 2005, returns over 3000 hits and covers a wide range of active agents and other materials.
In general, the freeze-drying or lyophilization technique is to dissolve, suspend, or emulsify a compound or formulation; freeze the resultant solution, suspension, or emulsion; and then to apply a vacuum thereto to sublimate/evaporate the solvents and other liquids in the frozen mass used to dissolve, suspend or emulsify the material. In many applications, the use of auxiliary agents to create suitable solutions, suspensions, and emulsions is not of significant concern. This is especially so where the auxiliary agent is acceptable to be present in the end product, as in the use of auxiliary food ingredients in freeze dried foods. Similarly, where pharmaceuticals are intended for oral ingestion, a wide range of auxiliary pharmaceutically acceptable agents may be used to aid in the preparation of lyophilized active compounds or formulations containing such active compounds. In most freeze-drying processes, a clear solution of the material to be freeze dried is obtained, if possible. This is then usually filtered aseptically to remove any extraneous solids and microorganism, and the filtered solution is filled into glass vials and cooled in a lyophilization chamber whereby the dissolved solids generally freeze together with the freezable liquid components, but may, depending upon concentration and the rate of the freezing process, begin to come out of solution during the process of cooling or freezing. For example, if one were to prepare a solution at its saturation concentration, the dissolved solid could precipitate during the freezing process. Depending upon the solvent or solvent combination used, there may be some liquid portion that does not freeze, but remains liquid and is distributed within the otherwise frozen mass. The application of vacuum pressures then permits the removal of unfrozen liquids first, followed by the sublimation of frozen liquid components, leaving behind a purer, dried product. In some techniques, the freezing process is done slowly so that crystallization takes place substantially before the solvent is frozen. In other techniques, the freezing step is performed rapidly to freeze the solvent before appreciable crystallization has occurred. In still other techniques, after freezing has taken place, addition of a small degree of heat to warm the frozen mass slightly permits the frozen liquid components to sublimate more readily. These same techniques may be applicable to situations when suspensions, emulsions, and complex formulations are involved, except that the filtering step may not be suitable because it may remove active or other auxiliary components which are intended to be present.
Unfortunately, the range of acceptable materials for use in pharmaceuticals that are intended for parenteral administration, is not as large and not so accommodating. For example, emulsions where the freeze-drying process leaves the emulsifier and/or the oil phase present in the lyophilizate would generally not be acceptable from an intravenous injection point of view. Similarly, suspending agents would also not be desirable. Thus, it is clear that an alternate lyophilization procedure that could eliminate the use of undesirable auxiliary agents to a larger degree than is presently available is desirable and sought after.
Although the prior art is replete with references to freeze-drying and lyophilization, most literature refers to the technique in a general manner such as “the material is freeze-dried as commonly practiced in the art” and other general statements of similar description. Virtually all of the references that do describe the details of the lyophilization process make no mention of, nor suggestion of, the use of an anti-solvent or non-solvent. Most references refer to clear solutions, solvents and co-solvents being used to obtain clarity or near clarity, with the solution then being filtered. Most references involving lyophilization, when discussing solvents, refer to aqueous materials.
Representative (non-exhaustive) patents and applications which are of note include the following, all of which are incorporated herein in their entirety. U.S. 2005/0049209 discusses freeze-drying of emulsions. U.S. Pat. No. 6,770,678 discusses that for freeze drying purposes it is desirable to have the solution concentration as high as possible, but often the high concentration leads to crystals forming during the cooling step, which the reference states is undesirable. U.S. 2004/0063792 mentions freeze-drying sertraline from a number of solvent/co-solvent combinations. U.S. 2004/0043042 discusses micro-lyophilization. U.S. 2003/0229027 mentions freeze-drying canabinoids from solvent mixtures in the presence of certain sugars. U.S. 2003/0202978 discusses spray freeze-drying. U.S. 2002/0010357; U.S. Pat. Nos. 6,384,259; 6,407,278; 6,841,545; and 6,489,312 all relate to amifostine lyophilizates. U.S. Pat. No. 6,566,329 discusses precipitating human growth hormone out of solution by adjusting the pH to the isoelectric point and then freeze-drying the result. U.S. Pat. No. 5,731,291 discusses using a solvent (water) and a second agent that sublimates at −40° C. in a lyophilization process. WO99/30688 discusses using an accelerant excipient to enhance the rate of solvent sublimation. WO2004/039804 discusses freeze-drying moxifloxacin from water. The specification mentions that it can also be obtained by use of an anti-solvent followed by filtration, decantation, or centrifugation. There is no suggestion that the moxifloxacin obtained from the solution by use of an anti-solvent then be subjected to freeze drying. U.S. 2003/082236 discusses use of a supercritical anti-solvent.